Therapeutic composition



Patented Aug. 3, 1954 UNITED FATENT OFFICE THERAPEUTIC COMPOSITION Charles Harmon Tilford, Cincinnati, and Marcus -George Van Campen, Jr., Wyoming, Ohio, as-

- .signors to The Wm. S. Merrcll Company, Cincinnati, Ohio, a corporation of Delaware No Drawing. Application February 19, 1952, Serial No. 272,524

Claims. 1 This invention relates to new compounds which are useful as antispasmodics, having antispasmedic action on normal smooth muscle as well '2 The invention will be further illustrated by the following specific examples, but it is not limited thereto.

as against neurotropic and musculotropic spasms EXAMPLE I of f. f g des'plte Fhelr i 5 Beta-diethylaminoethyl I-(Z-thz'enyl) -cycloac lvi y, are re.a ively free rom undesirable s1 e hexanecarboxylate reactions and have a suitable low toxicity. They are also useful as antiiungal agents.

The new compounds of the invention are 1- thienyl-cycloaalkanecarboxylic acid esters of tertiary amino alcohols. They may be represented I \'U Dn in which n is a number from 1 to 4, R and R are alkyl groups of l to 3 carbon atoms (which may be alike or diflerent) or together form an alkylene radical which with thenitrogen forms a cyclic radical'as in the 'piper-idino compounds, such radical having not more than 6 carbon atoms; and in which the radical-designated by alkylene is a lower alkylene radical such as methyl, ethyl, nepropyl, isopropyl or the like. These compounds are basic in nature, and although they may be produced in the form of the free base, will ordinarily housed in the form of a salt, such as the phosphate, sulfate, tartrate, glycolate, levulinate or the like, but usually as the hydrochloride.

These new compounds are conveniently prepared by re-esterifioation-of the corresponding alkyl esters, for example, the ethyl ester, with. the selected tertiary amino alcohol, with separation of liberated alcohol by distillation, using an inert solvent such as xylene and a catalyst, such as sodium, the alkyl ester in turn being produced by the acid aicoholysis of the'corresponding nitrile. This method of preparation is illustrated by the following type equation:

To 600 ml. of liquid ammonia containing 0.8 gram of ferricnitrate were added 29.9 grams of freshly cut'sodium over a period of 30 to 40 minutes. '75 grams of2-thienylacetonitrile Werethen by the formula added with stirring. The mixture was cooled to -50 C. and 138 grams of pentamethylene bro- GH? CO0'a1kY1ene*NRR' mide and 5.00 ml. of dry ether were added over 15 a period of one hour. The reaction mixture was slowly heated and finally refluxed for 4 hours. About 500 ml. of water were then cautiously added. The ether layer which formed was separated, dried over sodium sulfate and fractionally distilled. l- (Z-thienyD-cyclohexyl cyanide was collected at 102 to 104 C./0.28 mm. 1'7 grams of this cyanide, 125 ml. of ethyl alcohol and 2-5 ml. of concentrated sulfuric acid were refluxed for 72 to 96 hours. The reaction product was then poured into a vessel containing 3.00 grams of ice and the oil that. separated was extracted with toluene and fractionally distilled. .Fthyl 1-(2- thienyl)-cyclohexanecarboxylate was collected at 119 to 124 0/026 mm. 9 grams of this ester, 9 grams of beta-diethylaminoethanol and 30 ml. of xylene were then introduced into aflask and about 5 ml. of distillate taken ofi to remove any water. 0.5 gram of sodium was added. The tolucue-ethanol binary mixture was slowly distilled on" at 68 C. After anhour, no more distillate came over at this temperature so the reaction mixture was distilled up to a temperature of 80 C. at a pressure of 20 mm. to remove any volatile materials. The residue Was taken up in 100 ml. of petroleum ether, and washed with water. Alcoholic HCl was then added until the mixture was acid to Congo red. The crude, solid beta-diethylaminoethyl l-(Z-thienyl) cyclohexanecarboxylate hydrochloride was collected on a filter. On recrystallization from butanone it gave a product acid melting at 139 to 140 C. (uncorrected). I EXAMPLE 11 l I Following the procedure of Example I, but using s beta-dimethylaminoethanol (in equivalent molar 0H, 000R proportions) instead of the beta-diethylamino- I C H0 alkylene NRR (CH5; I

alkyleno NR R ethanol gave beta-dimethyl-aminoethyl 1-(2- thienyl)-cyclohexanecarboxylate hydrochloride, melting at 135 to 137 C. (uncorrected).

EXAIWPLE HI Following the procedure of Example I but using 129.6 grams of tetramethylene bromide instead of the pentamethylene bromide gave an intermediate 1- (Z-thienyl) -cyclopentyl cyanide distilling at to 98 C./0.3 mm., an intermediate ethyl 1-(2- thienyl) cyclopentanecarboxylate distilling at 145 to 150 C./ 16 mm.. and a final betadiethylaminoethyl 1- (Z-thienyl) cyclc-pentanecarboxylate hydrochloride melting at 118 to 121 C. (uncorrected) Other 1-thienyl-cycloalkanecarboxylate tertiary amino alcohol esters included in the invention are:

Dimethylaminomethyl 1- (2-thienyl) cyclobutylcarboxylate.

Dimethylaminopropyl 1- (3-thienyl) -cyclohexylcarboxylate.

Methylethylaminoethyl 1- S-thienyl) -cyclopentyl-carboxylate.

Piperidinomethyl 1 (Z-thienyl)cyclopropy1carboxylate.

Dipropylaminoethyl 1- (Z-thienyl) -cyclohexylcarboxylate.

Diethylaminoisopropyl 1- (Z-thienyl) cyclohcxyl carboxylate.

The antifungal activity of the compounds was demonstrated by a comparison of the antiiungal activity of diphenylpyraline (1-methyl-4-benzhy dryloXy-piperidine of the formula as a standard of comparison) against Candida albicans Cryptococcus neoformans Nocardic asteriodes Micosporum audouim' Trycophyton rubmm Trycophyton mentagrop'hytes Histoplasma capsulatum Blastomyces dermatiditis The diphenylpyraline showed. substantially less activity than each of the other three compounds.

We claim: 1. Compounds of the formula l (CH2),

in which as is a number from 1 to 4, the radical NRR is selected from the group consisting of dialkylamino radicals in which the alkyl groups have not more than 3 carbon atoms and cyclic radicals in which RR represents an alkylene chain having not more than 6 carbon atoms and R" is a divalent group of the formula (CnHZn) in which n is an integer not greater than 4.

2. Compounds of the formula CH2 OOORNRR References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 2,541,024 Blicke Feb. 13, 1951 2,541,634 Blicke -1 Feb. 13, 1951 2,561,385 Leonard July 24, 1951 OTHER REFERENCES I-Iuttrer, Enzymologia, 12, 308-9 (1948).

Powers, Advancing Fronts in Chem., 1946, p. 33.

Whitmore, Org. Chem., pp. 884, 893, Van Nostrand, N. Y., 1937.

Richter, Organic Chem, pp. 649-50, Wiley, N. Y., 1938.

Williams, Detoxication Mechanisms, p. 194, Wiley, N. Y., 1947.

Lands, Proc. Soc. Exp. Bio. Med. 57, -6 (1944).

Alles, J. Pharm. Exp. Ther. 72, 265 (1941).

Caesar and Sachanen, Ind. Eng. Chem. 40, 922 (1948).

Steinkopf, The Chemie des Thiophens, p. 21, Edwards Lithoprint of 1941 publication.

Viaud, Products Pharm. 2, 58, Feb. 1947.

Le Suer, 3-Substituted Thiophenes, Doctorate Thesis, 1). 2, Dept. of Chem., Indiana Univ., Call No. QB 1000 L 644.

Karrer, Organic Chemistry, Elsevier Pub. 00., 1946, 2nd Eng. Ed, pp. -190. 

1. COMPOUNDS OF THE FORMULA 